Cannabinoids have been shown to have anticonvulsant properties, but no studies have evaluated the effects of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy (AE) and status epilepticus (SE). This study investigated the anticonvulsant properties of the cannabinoid receptor agonist R()-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolol[1,2,3 de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone (WIN 55,212-2) in primary hippocampal neuronal culture models of both AE and SE. WIN 55,212-2 produced dose-dependent anticonvulsant effects against both spontaneous recurrent epileptiform discharges (SRED) (EC50 0.85 M) and SE (EC50 1.51 M), with total suppression of seizure activity at 3 M and of SE activity at 5 M. The anticonvulsant properties of WIN 55,212-2 in these preparations were...

Neuroligins are postsynaptic cell-adhesion molecules that interact with presynaptic neurexins. Rare mutations in neuroligins and neurexins predispose to autism, including a neuroligin-3 amino acid substitution (R451C) and a neuroligin-3 deletion. Previous analyses showed that neuroligin-3 R451C-knockin mice exhibit robust synaptic phenotypes but failed to uncover major changes in neuroligin-3 knockout mice, questioning the notion that a common synaptic mechanism mediates autism pathogenesis in patients with these mutations. Here, we used paired recordings in mice carrying these mutations to measure synaptic transmission at GABAergic synapses formed by hippocampal parvalbumin- and cholecystokinin-expressing basket cells onto pyramidal neurons. We demonstrate that in addition to unique gain-of-function effects...

Cannabinoids have been shown to critically modulate cholinergic neurotransmission in the hippocampus, yet opposing effects of cannabinoid receptor 1 (CB1R) agonists on hippocampal synaptic acetylcholine (ACh) efflux have been reported. This study shows that administration of a synthetic CB1R agonist results in a biphasic, dose-dependent, effect on hippocampal ACh: a low (0.5 mg/kg, i.p.) and a high (5 mg/kg, i.p) dose of WIN55,212-2 induces a transient stimulation and a prolonged inhibition of hippocampal ACh efflux, respectively. Both effects of WIN55,212-2 are mediated through CB1 receptors coupled to Gi but involve different neuroanatomical sites. Thus, intrahippocampal infusion of the CB1R antagonist SR141716A or pertussis toxin...

Peroxisome proliferator-activated receptor-c (PPARc) has been reported to be involved in the etiology of pathological features of Alzheimer’s disease (AD). Cannabidiol (CBD), a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARc, which has been recently indicated as its putative binding site. CBD actions on bamyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade...

Cannabinoids and the endocannabinoid system have attracted considerable interest for therapeutic applications. Nevertheless, the mechanism of action of one of the main nonpsychoactive phytocannabinoids, cannabidiol (CBD), remains elusive despite potentially beneficial properties as an anti-convulsant and neuroprotectant. Here, we characterize the mechanisms by which CBD regulates Ca 2 homeostasis and mediates neuroprotection in neuronal preparations. Imaging studies in hippocampal cultures using fura-2 AM suggested that CBD-mediated Ca 2 regulation is bidirectional, depending on the excitability of cells. Under physiological K /Ca 2 levels, CBD caused a subtle rise in [Ca 2]i , whereas CBD reduced [Ca 2]i and prevented Ca 2 oscillations under high-excitability...

BACKGROUND AND PURPOSE Phytocannabinoids in Cannabis sativa have diverse pharmacological targets extending beyond cannabinoid receptors and several exert notable anticonvulsant effects. For the first time, we investigated the anticonvulsant profile of the phytocannabinoid cannabidivarin (CBDV) in vitro and in in vivo seizure models. EXPERIMENTAL APPROACH The effect of CBDV (1–100 mM) on epileptiform local field potentials (LFPs) induced in rat hippocampal brain slices by 4-aminopyridine (4-AP) application or Mg2+ -free conditions was assessed by in vitro multi-electrode array recordings. Additionally, the anticonvulsant profile of CBDV (50–200 mg·kg-1 ) in vivo was investigated in four rodent seizure models: maximal electroshock (mES) and audiogenic seizures in...

We examined whether acetylcholine release in the hippocampus and striatum and noradrenaline release in the hippocampus is altered in CB1 receptor-de®cient mice. The electrically evoked tritium over¯ow from hippocampal slices preincubated with [3 H]-choline was increased by about 100% in CB1 7/7 compared to CB1 +/+ mice whereas the electrically evoked tritium over¯ow from striatal slices preincubated with [3 H]-choline and from hippocampal slices preincubated with [3 H]- noradrenaline did not di€er. The cannabinoid receptor agonist, WIN 55,212-2, inhibited, and the CB1 receptor antagonist, SR 141716, facilitated, the evoked tritium over¯ow from hippocampal slices (preincubated with [3 H]-choline) from CB1 +/+ as opposed to...

A nascent literature has postulated endocannabinoids (eCBs) as strong sleep-inducing lipids, particularly rapid-eye-movement sleep (REMs), nevertheless the exact mechanisms behind this effect remain to be determined. Anandamide and 2-arachidonyl glycerol, two of the most important eCBS, are synthesized in the hippocampus. This structure also expresses a high concentration of cannabinoid receptor 1 (CB1). Recent extensive literature supports eCBs as important regulators of hippocampal activity. It has also been shown that these molecules vary their expression on the hippocampus depending on the light–dark cycle. In this context we decided to analyze the effect of intrahippocampal administration of the eCB anandamide (ANA) on the sleep–waking cycle...

Cannabinoids, the active components of marijuana and their endogenous counterparts, act on the brain and many other organs through the widely expressed CB1 cannabinoid receptor. In contrast, the CB2 cannabinoid receptor is abundant in the immune system and shows a restricted expression pattern in brain cells. CB2-selective agonists are, therefore, very attractive therapeutic agents as they do not cause CB1-mediated psychoactive effects. CB2 receptor expression in brain has been partially examined in differentiated cells, while its presence and function in neural progenitor cells remain unknown. Here we show that the CB2 receptor is expressed, both in vitro and in vivo, in neural progenitors from...

To understand the functional significance and mechanisms of action in the CNS of endogenous and exogenous cannabinoids, it is crucial to identify the neural elements that serve as the structural substrate of these actions. We used a recently developed antibody against the CB1 cannabinoid receptor to study this question in hippocampal networks. Interneurons with features typical of basket cells showed a selective, intense staining for CB1 in all hippocampal subfields and layers. Most of them (85.6%) contained cholecystokinin (CCK), which corresponded to 96.9% of all CCK-positive interneurons, whereas only 4.6% of the parvalbumin (PV)-containing basket cells expressed CB1. Accordingly, electron microscopy revealed that CB1-immunoreactive...